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Human radical scavenger α1-microglobulin protects against hemolysis in vitro and α1-microglobulin knockout mice exhibit a macrocytic anemia phenotype

Kristiansson, Amanda LU ; Bergwik, Jesper LU ; Alattar, Abdul Ghani LU orcid ; Flygare, Johan LU ; Gram, Magnus LU orcid ; Hansson, Stefan R LU orcid ; Olsson, Martin L LU orcid ; Storry, Jill R LU ; Allhorn, Maria LU and Åkerström, Bo LU (2021) In Free Radical Biology & Medicine 162.
Abstract

During red blood cell (RBC) lysis hemoglobin and heme leak out of the cells and cause damage to the endothelium and nearby tissue. Protective mechanisms exist; however, these systems are not sufficient in diseases with increased extravascular hemolysis e.g. hemolytic anemia. α1-microglobulin (A1M) is a ubiquitous reductase and radical- and heme-binding protein with antioxidation properties. Although present in the circulation in micromolar concentrations, its function in blood is unclear. Here, we show that A1M provides RBC stability. A1M-/- mice display abnormal RBC morphology, reminiscent of macrocytic anemia conditions, i.e. fewer, larger and more heterogeneous cells. Recombinant human A1M (rA1M) reduced in vitro hemolysis of murine... (More)

During red blood cell (RBC) lysis hemoglobin and heme leak out of the cells and cause damage to the endothelium and nearby tissue. Protective mechanisms exist; however, these systems are not sufficient in diseases with increased extravascular hemolysis e.g. hemolytic anemia. α1-microglobulin (A1M) is a ubiquitous reductase and radical- and heme-binding protein with antioxidation properties. Although present in the circulation in micromolar concentrations, its function in blood is unclear. Here, we show that A1M provides RBC stability. A1M-/- mice display abnormal RBC morphology, reminiscent of macrocytic anemia conditions, i.e. fewer, larger and more heterogeneous cells. Recombinant human A1M (rA1M) reduced in vitro hemolysis of murine RBC against spontaneous, osmotic and heme-induced stress. Moreover, A1M is taken up by human RBCs both in vitro and in vivo. Similarly, rA1M also protected human RBCs against in vitro spontaneous, osmotic, heme- and radical-induced hemolysis as shown by significantly reduced leakage of hemoglobin and LDH. Addition of rA1M resulted in decreased hemolysis compared to addition of the heme-binding protein hemopexin and the radical-scavenging and reducing agents ascorbic acid and Trolox (vitamin E). Furthermore, rA1M significantly reduced spontaneous and heme-induced fetal RBC cell death. Addition of A1M to human whole blood resulted in a significant reduction of hemolysis, whereas removal of A1M from whole blood resulted in increased hemolysis. We conclude that A1M has a protective function in reducing hemolysis which is neither specific to the origin of hemolytic insult, nor species specific.

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organization
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type
Contribution to journal
publication status
published
subject
in
Free Radical Biology & Medicine
volume
162
publisher
Elsevier
external identifiers
  • pmid:32092412
  • scopus:85081275109
ISSN
0891-5849
DOI
10.1016/j.freeradbiomed.2020.02.018
language
English
LU publication?
yes
id
87f821b3-1007-4212-892e-a1d0b0e831b8
date added to LUP
2020-02-28 13:48:22
date last changed
2024-04-17 04:33:50
@article{87f821b3-1007-4212-892e-a1d0b0e831b8,
  abstract     = {{<p>During red blood cell (RBC) lysis hemoglobin and heme leak out of the cells and cause damage to the endothelium and nearby tissue. Protective mechanisms exist; however, these systems are not sufficient in diseases with increased extravascular hemolysis e.g. hemolytic anemia. α1-microglobulin (A1M) is a ubiquitous reductase and radical- and heme-binding protein with antioxidation properties. Although present in the circulation in micromolar concentrations, its function in blood is unclear. Here, we show that A1M provides RBC stability. A1M-/- mice display abnormal RBC morphology, reminiscent of macrocytic anemia conditions, i.e. fewer, larger and more heterogeneous cells. Recombinant human A1M (rA1M) reduced in vitro hemolysis of murine RBC against spontaneous, osmotic and heme-induced stress. Moreover, A1M is taken up by human RBCs both in vitro and in vivo. Similarly, rA1M also protected human RBCs against in vitro spontaneous, osmotic, heme- and radical-induced hemolysis as shown by significantly reduced leakage of hemoglobin and LDH. Addition of rA1M resulted in decreased hemolysis compared to addition of the heme-binding protein hemopexin and the radical-scavenging and reducing agents ascorbic acid and Trolox (vitamin E). Furthermore, rA1M significantly reduced spontaneous and heme-induced fetal RBC cell death. Addition of A1M to human whole blood resulted in a significant reduction of hemolysis, whereas removal of A1M from whole blood resulted in increased hemolysis. We conclude that A1M has a protective function in reducing hemolysis which is neither specific to the origin of hemolytic insult, nor species specific.</p>}},
  author       = {{Kristiansson, Amanda and Bergwik, Jesper and Alattar, Abdul Ghani and Flygare, Johan and Gram, Magnus and Hansson, Stefan R and Olsson, Martin L and Storry, Jill R and Allhorn, Maria and Åkerström, Bo}},
  issn         = {{0891-5849}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Free Radical Biology & Medicine}},
  title        = {{Human radical scavenger α1-microglobulin protects against hemolysis in vitro and α1-microglobulin knockout mice exhibit a macrocytic anemia phenotype}},
  url          = {{http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.018}},
  doi          = {{10.1016/j.freeradbiomed.2020.02.018}},
  volume       = {{162}},
  year         = {{2021}},
}